tbuckley/cabot-search huggingface dataset:
<scp>HERVs</scp> characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy
Authors: Vincent Alcazer, Paola Bonaventura, Laurie Tonon, Emilie Michel, Virginie Mutez, Clémentine Fabres, Nicolas Chuvin, Rasha Boulos, Yann Estornes, Véronique Maguer‐Satta, Kevin Geistlich, Alain Viari, Klaus H. Metzeler, Wolfgang Hiddemann, Aarif M. N. Batch, Tobias Herold, Christophe Caux, Stéphane Depil
Journal: American Journal of Hematology (2022)

Abstract Human endogenous retroviruses (HERVs) represent 8% of the human genome. The expression of HERVs and their immune impact have not been extensively studied in Acute Myeloid Leukemia (AML). In this study, we used a reference of 14 968 HERV functional units to provide a thorough analysis of HERV expression in normal and AML bone marrow cells. We show that the HERV retrotranscriptome accurately characterizes normal and leukemic cell subpopulations, including leukemia stem cells, in line with different epigenetic profiles. We then show that HERV expression delineates AML subtypes with different prognoses. We finally propose a method to select and prioritize CD8 + T cell epitopes derived from AML‐specific HERVs and we show that lymphocytes infiltrating patient bone marrow at diagnosis contain naturally occurring CD8 + T cells against these HERV epitopes. We also provide in vitro data supporting the functionality of HERV‐specific CD8 + T‐cells against AML cells. These results show that HERVs represent an important source of genetic information that can help enhancing disease stratification or biomarker identification and an important reservoir of alternative tumor‐specific T cell epitopes relevant for cancer immunotherapy.
Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells
Authors: Rob S. Sellar, Adam S. Sperling, Mikołaj Słabicki, Jessica A. Gasser, Marie E. McConkey, Katherine A. Donovan, Nada Mageed, Dylan N. Adams, Charles Zou, Peter G. Miller, Ravi K. Dutta, Steffen Boettcher, Amy E. Lin, Brittany Sandoval, Vanessa A. Quevedo Barrios, Veronica Kovalcik, Jonas Koeppel, Elizabeth K. Henderson, Emma C. Fink, Lu Yang, Anthony Chan, Sheela Pangeni Pokharel, Erik J. Bergstrom, Rajan Burt, Namrata D. Udeshi, Steven A. Carr, Eric S. Fischer, Chun-Wei Chen, Benjamin L. Ebert
Journal: Journal of Clinical Investigation (2022)

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR/Cas9 screens implicated decreased translation initiation as protective following GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to the effects of GSPT1 degradation. We defined 2 Crbn amino acids that prevent Gspt1 degradation in mice, generated a knockin mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant acute myeloid leukemia.
KMT2D-NOTCH Mediates Coronary Abnormalities in Hypoplastic Left Heart Syndrome
Authors: Zhiyun Yu, Xin Zhou, Ziyi Liu, Victor Pastrana-Gomez, Yu Liu, Minzhe Guo, Lei Tian, Timothy J. Nelson, Nian Wang, Seema Mital, David Chitayat, Joseph C. Wu, Marlene Rabinovitch, Sean M. Wu, Michael P. Snyder, Yifei Miao, Mingxia Gu
Journal: Circulation Research (2022)
Remotely delivered cognitive behavioural and personalised exercise interventions for fatigue severity and impact in inflammatory rheumatic diseases (LIFT): a multicentre, randomised, controlled, open-label, parallel-group trial
Authors: Eva-Maria Bachmair, Kathryn Martin, Lorna Aucott, Neeraj Dhaun, Emma Dures, Richard Emsley, Stuart R Gray, Elizabeth Kidd, Vinod Kumar, Karina Lovell, Graeme MacLennan, Paul McNamee, John Norrie, Lorna Paul, Jon Packham, Stuart H Ralston, Stefan Siebert, Alison Wearden, Gary Macfarlane, Neil Basu
Journal: The Lancet Rheumatology (2022)

Chronic fatigue is a poorly managed problem in people with inflammatory rheumatic diseases. Cognitive behavioural approaches (CBA) and personalised exercise programmes (PEP) can be effective, but they are not often implemented because their effectivenesses across the different inflammatory rheumatic diseases are unknown and regular face-to-face sessions are often undesirable, especially during a pandemic. We hypothesised that remotely delivered CBA and PEP would effectively alleviate fatigue severity and life impact across inflammatory rheumatic diseases.LIFT is a multicentre, randomised, controlled, open-label, parallel-group trial to assess usual care alongside telephone-delivered CBA or PEP against usual care alone in UK hospitals. Patients with any stable inflammatory rheumatic disease were eligible if they reported clinically significant, persistent fatigue. Treatment allocation was assigned by a web-based randomisation system. CBA and PEP sessions were delivered over 6 months by trained health professionals in rheumatology. Coprimary outcomes were fatigue severity (Chalder Fatigue Scale) and impact (Fatigue Severity Scale) at 56 weeks. The primary analysis was by full analysis set. This study was registered at ClinicalTrials.gov (NCT03248518).From Sept 4, 2017, to Sept 30, 2019, we randomly assigned and treated 367 participants to PEP (n=124; one participant withdrew after being randomly assinged), CBA (n=121), or usual care alone (n=122), of whom 274 (75%) were women and 92 (25%) were men with an overall mean age of 57·5 (SD 12·7) years. Analyses for Chalder Fatigue Scale included 101 participants in the PEP group, 107 in the CBA group, and 107 in the usual care group and for Fatigue Severity Scale included 101 in PEP, 106 in CBA, and 107 in usual care groups. PEP and CBA significantly improved fatigue severity (Chalder Fatigue Scale; PEP: adjusted mean difference -3·03 [97·5% CI -5·05 to -1·02], p=0·0007; CBA: -2·36 [-4·28 to -0·44], p=0·0058) and fatigue impact (Fatigue Severity Scale; PEP: -0·64 [-0·95 to -0·33], p<0·0001; CBA: -0·58 [-0·87 to -0·28], p<0·0001); compared with usual care alone at 56 weeks. No trial-related serious adverse events were reported.Telephone-delivered CBA and PEP produced and maintained statistically and clinically significant reductions in the severity and impact of fatigue in a variety of inflammatory rheumatic diseases. These interventions should be considered as a key component of inflammatory rheumatic disease management in routine clinical practice.Versus Arthritis.
Comparison of trends in Clostridioides difficile infections in hospitalised patients during the first and second waves of the COVID-19 pandemic: A retrospective sentinel surveillance study
Authors: Karuna E.W. Vendrik, Amoe Baktash, Jelle J. Goeman, Céline Harmanus, Daan W. Notermans, Sabine C. de Greeff, Ed J. Kuijper
Journal: The Lancet Regional Health - Europe (2022)

During the COVID-19 pandemic, several factors, such as improved hand hygiene, social distancing, and restricted hospital referral, may have had an influence on the epidemiology of Clostridioides difficile infections (CDI).The annual CDI incidence rate of nine hospitals participating in the Dutch sentinel CI surveillance with complete data was compared between 2020 and the previous five surveillance years. Trends in characteristics of hospitalised CDI patients in 21-24 participating hospitals were compared between the first (March 13-May 12, 2020) or second Dutch COVID-19 wave (September 17, 2020-January 1, 2021) and the same calendar periods in 2015 through 2019. All analyses were adjusted for trend changes over time.The annual CDI incidence rate in 2020 was lower compared to previous years. During the second wave, the percentage of CDI patients with severe CDI was higher compared to earlier (25·8% in 2020 vs 17·9% in 2015-2019 (RR 1·6; 95%CI 1·1-2·3)). After adjustment for delayed C. difficile diagnostics (≥8 days from start symptoms), the increase disappeared. Delayed C. difficile diagnostics was indeed more common during the second wave (RR 1·7; 95%CI 1·1-2·6), but only for community-onset CDI (CO-CDI).This study shows that a higher percentage of severe CDI cases was observed during the second COVID-19 wave. This may partially be caused by delayed diagnostics, potentially due to decreased visits to a physician or restricted hospital referral for CO-CDI patients.Dutch ministry of Health.
Commentary on Long-term Effectiveness of Adjuvant Treatment in Parkinson Disease—Reply
Authors: Richard Gray, Crispin Jenkinson, Carl E. Clarke
Journal: JAMA Neurology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
SHR2554, an EZH2 inhibitor, in relapsed or refractory mature lymphoid neoplasms: a first-in-human, dose-escalation, dose-expansion, and clinical expansion phase 1 trial
Authors: Yuqin Song, Yanyan Liu, Zhi-Ming Li, Lanfang Li, Hang Su, Zhengming Jin, Xuelan Zuo, Jianyuan Wu, Hui Zhou, Kunyan Li, Chuan He, Jianfeng Zhou, Junyuan Qi, Siguo Hao, Zhen Cai, Yijing Li, Weiwei Wang, Xiaojing Zhang, Jianjun Zou, Jun Zhu
Journal: The Lancet Haematology (2022)
POS0612 COMORBIDITIES IN RHEUMATOID ARTHRITIS DO NOT INFLUENCE BIOLOGICS DRUG RETENTION: DATA FROM THE NATIONAL HEALTH INSURANCE FUND OF TUNIS
Authors: S. Boussaid, K. Saadaoui, S. Rekik, S. Jemmali, S. Rahmouni, H. Sahli, M. Elleuch
Journal: Annals of the Rheumatic Diseases (2022)

Background The advent of biologics in the late 1990s radically changed the profile of inflammatory diseases, in particular rheumatoid arthritis (RA). The survival of these innovative therapies is an indicator, in clinical practice, of their long-term efficiency in patients with RA. Objectives To study the influence of comorbidities on biologics drugs retention rates. Methods We conducted a cross-sectional, observational study. Data were identified from the files of the National Health Insurance Fund of Tunis. It included patients with RA on biologics. Epidemiological characteristics such as age, sex, and comorbidities, were collected. Comorbidities were assessed by the Charlson Comorbidity Index (CCI). The therapeutic maintenance rate at 12, 24, 36, and 48 months as well as the biologics survival were analyzed using Kaplan-Meier survival curves and compared using the Log-Rank test. Results Three hundred and seventy-four files were selected. The average age of our cohort was 55±12.54 years [20-90]. A female predominance was noted with a sex ratio M/F=0.147. The average duration of RA was 11.7±6.76 years [2-41].First biogics prescription was: etanercept 54%, adalimumab 14%, certolizumab pegol 13%, infliximab 6%, tocilizumab 6% and rituximab 7%. First-line survival rates at 12, 24, 36, and 48 months were 85.8; 69.9; 60.6, and 55.9% respectively. Biologics drug survival was, on average, 41.7 months [39.47-43.91]. Comorbidities were assessed by the CCI in 373 patients (99.7%). Ninety patients had an ICC of 0 and 103 patients had an ICC of 1. Only one patient had an ICC of 8. The median value of this score was equal to 1, the mean was 1.64 ± 1.48. Osteoporosis was the most observed comorbidity with 78 patients (20.9%). The study of drug survival according to the ICC did not show any significant difference between the different curves (p=0.809). The Hazard Ratio was 0.999. Similarly, we did not find a discriminating threshold for the Charlson score, allowing it to be decisive for the survival of biologic drugs. Conclusion This study did not identify the influence of comorbidities on the biologics survival during RA. Comorbidities can have an impact not only on our therapeutic choice but also on the efficacy and maintenance of biomedicines as well as the quality of life of patients and consequently the prognosis of RA (1). The few studies that have looked at this subject have produced variable results. References [1]Estíbaliz Loza, Cristina Lajas, Jose Luis Andreu, Alejandro Balsa, et al. Consensus statement on a framework for the management of comorbidity and extra-articular manifestations in rheumatoid arthritis. Rheumatol Int 2015 Mar;35(3):445-58. Disclosure of Interests None declared
How better pandemic and epidemic intelligence will prepare the world for future threats
Authors: Oliver W. Morgan, Philip Abdelmalik, Enrique Perez-Gutierrez, Ibrahima Socé Fall, Masaya Kato, Esther Hamblion, Tamano Matsui, Pierre Nabeth, Richard Pebody, Jukka Pukkila, Mary Stephan, Chikwe Ihekweazu
Journal: Nature Medicine (2022)
Livedo Reticularis—A Presenting Sign of Neuromyelitis Optica Spectrum Disorder
Authors: Cleo Zarina Reyes, Negar Moheb, Jay Varrato
Journal: JAMA Neurology (2022)

This case report describes a man aged 58 years who presented with intermittent chest pain, numbness and tingling of the upper extremities, and a violaceous, reticular rash on his lower extremities, abdomen, and flank.
Evaluation of the inoculum effect of new antibiotics against carbapenem-resistant enterobacterales
Authors: Maxime Danjean, Claire Amaris Hobson, Maud Gits-Muselli, Céline Courroux, Audrey Monjault, Stéphane Bonacorsi, André Birgy
Journal: Clinical Microbiology and Infection (2022)

New antibiotics have been developed to treat multidrug-resistant Enterobacterales. We evaluated the impact of the inoculum size on minimal inhibitory concentrations (MICs) of recently commercialized antibiotics.We focused on 40 clinical carbapenemase-producing Enterobacterales and evaluated the impact of the inoculum size on the MICs to cefiderocol and to new β-lactams/β-lactamase inhibitors (ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam) at usual and high inocula (105 and 107 CFU/mL, respectively).At usual inoculum, 15% were resistant to cefiderocol (n = 6), 30% to meropenem-vaborbactam (n = 12), 42.5% to ceftazidime-avibactam (n = 17), 55% to imipenem-relebactam (n = 22), and 90% to ceftolozane-tazobactam (n = 36). At higher inoculum, a switch from susceptible to resistant category was observed for 88% (n = 30/34; CI, 71.6-96.2), 75% (n = 3/4; CI, 21.9-98.7), 72% (n = 13/18; CI, 46.4-89.3), 50% (n = 14/28; CI, 31.1-68.9), and 8.7% (n = 2/23; CI, 1.5-29.5) isolates regarding cefiderocol, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam, respectively.Cefiderocol and meropenem-vaborbactam were the most efficient against carbapenemase-producing Enterobacterales at usual inoculum. When increasing inoculum to 107 CFU/mL, all of the molecules were impacted, particularly cefiderocol and imipenem-relebactam, while others, such as ceftazidime-avibactam, remain mildly affected. Our in vitro results deserved to be confirmed in vivo.
Geographical Differences and Temporal Improvements in Forced Expiratory Volume in 1 Second of Preterm-Born Children
Authors: Sarah J. Kotecha, James T. D. Gibbons, Christopher W. Course, Emily E. Evans, Shannon J. Simpson, W. John Watkins, Sailesh Kotecha
Journal: JAMA Pediatrics (2022)

<h3>Importance</h3> Although preterm birth is associated with later deficits in lung function, there is a paucity of information on geographical differences and whether improvements occur over time, especially after surfactant was introduced. <h3>Objective</h3> To determine deficits in percentage predicted forced expiratory volume in 1 second (%FEV<sub>1</sub>) in preterm-born study participants, including those with bronchopulmonary dysplasia (BPD) in infancy, when compared with term-born control groups. <h3>Data Sources</h3> Eight databases searched up to December 2021. <h3>Study Selection</h3> Studies reporting spirometry for preterm-born participants with or without a term-born control group were identified. <h3>Data Extraction and Synthesis</h3> Data were extracted and quality assessed by 1 reviewer and checked by another. Data were pooled using random-effects models and analyzed using Review Manager and the R metafor package. <h3>Main Outcomes and Measures</h3> Deficits in %FEV<sub>1</sub>between preterm-born and term groups. Associations between deficits in %FEV<sub>1</sub>and year of birth, age, introduction of surfactant therapy, and geographical region of birth and residence were also assessed. <h3>Results</h3> From 16 856 titles, 685 full articles were screened: 86 with and without term-born control groups were included. Fifty studies with term controls were combined with the 36 studies from our previous systematic review, including 7094 preterm-born and 17 700 term-born participants. Of these studies, 45 included preterm-born children without BPD, 29 reported on BPD28 (supplemental oxygen dependency at 28 days), 26 reported on BPD36 (supplemental oxygen dependency at 36 weeks' postmenstrual age), and 86 included preterm-born participants. Compared with the term-born group, the group of all preterm-born participants (all preterm) had deficits of %FEV<sub>1</sub>of −9.2%; those without BPD had deficits of −5.8%, and those with BPD had deficits of approximately −16% regardless of whether they had BPD28 or BPD36. As year of birth increased, there was a statistically significant narrowing of the difference in mean %FEV<sub>1</sub>between the preterm- and term-born groups for the all preterm group and the 3 BPD groups but not for the preterm-born group without BPD. For the all BPD group, when compared with Scandinavia, North America and western Europe had deficits of −5.5% (95% CI, −10.7 to −0.3;<i>P</i> = .04) and −4.1% (95% CI, −8.8 to 0.5;<i>P</i> = .08), respectively. <h3>Conclusions and Relevance</h3> Values for the measure %FEV<sub>1</sub>were reduced in preterm-born survivors. There were improvements in %FEV<sub>1</sub>over recent years, but geographical region had an association with later %FEV<sub>1</sub>for the BPD groups.
Thiol-ene conjugation of a VEGF peptide to electrospun scaffolds for potential applications in angiogenesis
Authors: Tianyu Yao, Honglin Chen, Rong Wang, Rebeca Rivero, Fengyu Wang, Lilian Kessels, Stijn M. Agten, Tilman M. Hackeng, Tim G.A.M. Wolfs, Daidi Fan, Matthew B. Baker, Lorenzo Moroni
Journal: Bioactive Materials (2022)

Vascular endothelial growth factor (VEGF) plays a vital role in promoting attachment and proliferation of endothelial cells, and induces angiogenesis. In recent years, much research has been conducted on functionalization of tissue engineering scaffolds with VEGF or VEGF-mimetic peptide to promote angiogenesis. However, most chemical reactions are nonspecific and require organic solvents, which can compromise control over functionalization and alter peptide/protein activity. An attractive alternative is the fabrication of functionalizable electrospun fibers, which can overcome these hurdles. In this study, we used thiol-ene chemistry for the conjugation of a VEGF-mimetic peptide to the surface of poly (ε-caprolactone) (PCL) fibrous scaffolds with varying amounts of a functional PCL-diacrylate (PCL-DA) polymer. 30% PCL-DA was selected due to homogeneous fiber morphology. A VEGF-mimetic peptide was then immobilized on PCL-DA fibrous scaffolds by a light-initiated thiol-ene reaction. 7-Mercapto-4-methylcoumarin, RGD-FITC peptide and VEGF-TAMRA mimetic peptide were used to validate the thiol-ene reaction with fibrous scaffolds. Tensile strength and elastic modulus of 30% PCL-DA fibrous scaffolds were significantly increased after the reaction. Conjugation of 30% PCL-DA fibrous scaffolds with VEGF peptide increased the surface water wettability of the scaffolds. Patterned structures could be obtained after using a photomask on the fibrous film. Moreover, in vitro studies indicated that scaffolds functionalized with the VEGF-mimetic peptide were able to induce phosphorylation of VEGF receptor and enhanced HUVECs survival, proliferation and adhesion. A chick chorioallantoic membrane (CAM) assay further indicated that the VEGF peptide functionalized scaffolds are able to promote angiogenesis in vivo. These results show that scaffold functionalization can be controlled via a simple polymer mixing approach, and that the functionalized VEGF peptide-scaffolds have potential for vascular tissue regeneration.
POS0361-PARE THE MEDIATING EFFECT OF PAIN CATASTROPHIZING ON WORK PRODUCTIVITY
Authors: C. Ines, A. Ben Tekaya, A. Gharbi, R. Leila, O. Saidane, S. Bouden, R. Tekaya, I. Mahmoud, L. Abdelmoula
Journal: Annals of the Rheumatic Diseases (2022)

Background Work disability is a major patient outcome for spondyloarthritis (SpA) patients since SpA mostly appears in younger adults. Objectives we examined the influence of catastrophizing as a negative psychological factor on work productivity and activity impairment in SpA. Methods We conducted a cross-sectional study over a 3 months period. We included patients treated with SpA (Assessment of SpondyloArthritis International Society (ASAS) 2009 criteria). Patients related data, and disease characteristics were collected. Pain catastrophizing were assessed by the pain catastrophizing score (PCS). Work productivity and activity impairment were evaluated by Work productivity and Activity Impairment Questionnaire (WPAI). WPAI score examined four aspects of the patient’s life: Absenteeism due to SpA and presenteism at work, work productivity loss and activity impairment. Results Sixteen SpA patients were enrolled (22 females and 38 males). Mean age was 39,4 years ± 11,08. Mean disease duration was 11,37 years ±7,23; 28 were unemployed. Among workers, absenteeism due to SpA was reported in 7 cases (21,9%). Mean absenteeism rate was 2,35% [0-20]. Both mean work productivity loss and mean activity impairment were 50,23% [20-90]. Mean PCS was 15,73 ± 13,893. Thirteen patients (21,7%) had PCS &gt;30 which indicates a clinically relevant level of catastrophizing, and only two of them reported absenteeism at work. PCS score was higher in patients with absenteeism (mean score=26), compared to patients without absenteeism (mean score=16,96), (p=0,166). Presenteeism was lower in patients with higher pain catastrophizing scores, without reaching a significant difference (p=0,066). A higher PCS was significantly correlated with a greater work productivity loss (p= 0,036, r=0,371) and greater activity impairment (p=0,005, r=0,36). Conclusion In our series, pain catastrophizing affected work productivity and daily activity in patients with SpA. Disclosure of Interests None declared